Low-normal FT4 in early pregnancy as an independent risk factor for GDM: a large-scale retrospective cohort study

Objective: To investigate the role of early pregnancy thyroid function in gestational diabetes mellitus (GDM) development and its influencing factors. Methods: This large-scale retrospective cohort study assessed the associations between early pregnancy thyroid hormones and GDM subtypes, as well as their non-linear relationship with oral glucose tolerance test (OGTT) glucose levels, using multivariate logistic regression and restricted cubic spline models. Subgroup analyses were conducted within the normal thyroid function range to evaluate the risk associated with low-normal FT4 levels. Results: A total of 40,682 pregnant women were included and classified into four groups based on glucose levels: isolated fasting hyperglycemia (IFH), isolated post-load hyperglycemia (IPH), combined hyperglycemia (CH), and normal glucose tolerance (NGT). Free thyroxine (FT4) showed strong capability in differentiating among the subtypes, while thyroid-stimulating hormone (TSH) had limited effects. Multivariate and non-linear analyses showed a J-shaped association between FT4 and fasting/1-hour OGTT glucose, with strong protection below 15.4 pmol/L. In contrast, TSH showed weaker associations without a clear threshold effect. Importantly, low-normal FT4 (11.6-15.4 pmol/L), even within the normal range, independently increased GDM risk, especially in nulliparous and overweight/obese women. Conclusion: FT4 is an independent risk factor for GDM, with parity and pre-pregnancy BMI serving as important effect modifiers. Even the low-normal FT4 levels are associated with a higher risk of developing GDM and macrosomia.